Scope and mechanistic investigations on the solvent-controlled regio- and stereoselective formation of enol esters from the ruthenium-catalyzed coupling reaction of terminal alkynes and carboxylic acids

Article abstract of DOI:10.1021/om9007357

The ruthenium-hydride complex (PCy₃)₂(CO)RuHCl was found to be a highly effective catalyst for the alkyne-to-carboxylic acid coupling reaction to give synthetically useful enol ester products. A strong solvent effect was observed for

Full text of DOI:10.1021/om9007357

Organometallics 2009, 28, 6585–6592 6585
DOI: 10.1021/om9007357
Scope and Mechanistic Investigations on the Solvent-Controlled
Regio- and Stereoselective Formation of Enol Esters from the
Ruthenium-Catalyzed Coupling Reaction of Terminal Alkynes and
Carboxylic Acids
Chae S. Yi* and Ruili Gao
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881
Received August 21, 2009
The ruthenium-hydride complex (PCy3)2(CO)RuHCl was found to be a highly effective catalyst for
the alkyne-to-carboxylic acid coupling reaction to give synthetically useful enol ester products. A
strong solvent effect was observed for the ruthenium catalyst in modulating the activity and
selectivity; the coupling reaction in CH2Cl2 led to the regioselective formation of gem-enol ester
products, while the stereoselective formation of (Z)-enol esters was obtained in THF. The coupling
reaction was found to be strongly inhibited by PCy3. The coupling reaction of both PhCO2H/
PhCtCD and PhCO2D/PhCtCH led to extensive deuterium incorporation on the vinyl positions of
the enol ester products. An opposite Hammett value was observed when the correlation of a series of
para-substituted p-X-C6H4CO2H (X = OMe, CH3, H, CF3, CN) with phenylacetylene was examined
in CDCl3 (F = þ0.30) and THF (F = -0.68). Catalytically relevant Ru-carboxylate and -vinylidene-
carboxylate complexes, (PCy3)2(CO)(Cl)Ru(κ2-O2CC6H4-p-OMe) and (PCy3)2(CO)(Cl)RuC-
(dCHPh)O2CC6H4-p-OMe, were isolated, and the structure of both complexes was completely
established by X-ray crystallography. A detailed mechanism of the coupling reaction involving a
rate-limiting C-O bond formation step was proposed on the basis of these kinetic and structural
studies. The regioselective formation of the gem-enol ester products in CH2Cl2 was rationalized
by a direct migratory insertion of the terminal alkyne via a Ru-carboxylate species, whereas the
stereoselective formation of (Z)-enol ester products in THF was explained by invoking a
Ru-vinylidene species.
Introduction
regio- and stereoselectivity in forming substituted enol es-
ters. Notable recent examples on the catalytic synthesis of
enol esters include Zr-catalyzed methylalumination of al-
kynes,5 Au-catalyzed intramolecular rearrangements of pro-
pargylic esters and alcohols,6 Cu-catalyzed oxidative
esterification of aldehydes with β-dicarbonyl compounds,7
and asymmetric coupling reaction of ketenes with aldehydes
by chiral Fe catalysts.8 From an industrial perspective of
increasing synthetic efficiency as well as for reducing waste
byproducts, catalytic methods for producing enol esters are
highly desired compared to the classical methods that utilize
stoichiometric amounts of strong base or toxic Hg salts.9
Transition metal-catalyzed alkyne-to-carboxylic acid cou-
pling reactions offer an attractive route to enol esters, but
Enol esters are a versatile class of precursors for a variety
of synthetically important organic transformations such as
cycloaddition,1 asymmetric hydrogenation,2 C-C bond
coupling,3 and Aldol- and Mannich-type condensation reac-
tions.4 Since enol esters can also serve as a synthon for
aldehydes and ketones, much research effort has been de-
voted to develop efficient catalytic methods to control both
*Corresponding author. E-mail: chae.yi@marquette.edu.
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Urabe, H.; Suzuki, D.; Sasaki, M.; Sato, F. J. Am. Chem. Soc. 2003, 125,
4036–4037. (c) Hara, H.; Hirano, M.; Tanaka, K. Org. Lett. 2008, 10, 2537–
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r
2009 American Chemical Society
Published on Web 10/30/2009
pubs.acs.org/Organometallics

6586 Organometallics, Vol. 28, No. 22, 2009
Yi and Gao
their synthetic potential has not been fully exploited in part
because the catalytic method typically produces a mixture of
gem- and (E)/(Z)-enol ester products.10 Considerable re-
search has been devoted to control both regio- and stereo-
selectivity of the enol ester products by modulating the steric
and electronic nature of the metal catalysts. Generally, late
transition metal catalysts have been found to be effective for
producing a mixture of (E)- and (Z)-enol esters from anti-
Markovnikov addition of carboxylic acids to terminal al-
kynes over gem-enol ester products,10,11 though the regiose-
lective formation of gem-enol esters has been achieved by
using Ru and Rh catalysts.12 Dixneuf and co-workers ele-
gantly showed the relationship between steric environment
of the ruthenium-phosphine catalysts and the stereoselective
formation of the (Z)-enol esters.13 In a subsequent study, the
same authors reported a regioselective 2:1 alkyne-to-car-
boxylic acid coupling reaction to form the dienyl esters by
using the Cp*Ru(COD)Cl catalyst, in which a ruthenacy-
clopentadiene complex was proposed as the key intermediate
species for the coupling reaction.14 Both intra- and inter-
molecular versions of the catalytic alkyne-to-carboxylic
coupling methods have been successfully applied to the
synthesis of complex organic molecules.15 Despite consider-
able synthetic and mechanistic progress, however, neither
the nature of reactive intermediate species nor controlling
factors for the formation of gem- vs (E)/(Z)-enol esters have
been clearly established.
We previously reported that the coordinatively unsatu-
rated ruthenium-hydride complex (PCy3)2(CO)RuHCl (1) is
a highly effective catalyst for the coupling reactions of
alkenes and alkynes.16 Both ruthenium-acetylide and -viny-
lidene complexes have been found to be the key species for
these coupling reactions.17 As part of ongoing efforts to
extend synthetic utility of the ruthenium-catalyzed alkyne
coupling reactions, we have been exploring the catalytic
activity of the ruthenium-hydride complexes toward the
coupling reactions of alkynes with heteroatom substrates.
In this article, we report a detailed scope and mechanistic
study of the ruthenium-catalyzed alkyne-to-carboxylic acid
coupling reaction, which provides new insights in mediating
solvent-controlled regio- and stereoselective formation of
the enol ester products.
Results and Discussion
Catalyst Survey and Reaction Scope. The catalytic activity
of selected ruthenium complexes was initially screened for
the coupling reaction of benzoic acid and 4-ethynylanisole
(eq 1). Among the selected ruthenium catalysts, complex 1
was found to exhibit uniquely high catalytic activity and
selectivity in giving the gem-enol ester product 2a within 5 h
at 95 °C in CH2Cl2 (Table 1). Both Ru3(CO)12 and Cp*Ru-
(PPh3)2Cl showed significant activity, but suffered from low
selectivity in forming the coupling products. The catalyst
Cp*Ru(COD)Cl, on the other hand, produced a mixture of
1:1 and 1:2 coupling products, which is in line with the
previously reported results on the formation of dienyl ester
products.14
Next, the solvent effect on the activity and selectivity
patterns of the catalyst was examined for the coupling
reaction of benzoic acid and 4-ethynylanisole (Table 2). A
remarkably strong solvent influence on the ruthenium cata-
lyst 1 was observed in modulating the formation of the enol
ester products. Thus, the coupling reaction in relatively
nonpolar and noncoordinating solvents tended to favor the
formation of geminal coupling product 2a over (E)- and (Z)-
3a, of which CH2Cl2 was found to be the best in producing
the geminal product 2a among these solvents (entry 4). In
contrast, among polar coordinating solvents, which tended
to favor the formation of (Z)-enol ester product (Z)-3a, THF
was found to be the most selective in giving (Z)-3a (entry 10).
It should be emphasized that the formation of 1:2 coupling
products was not observed from the coupling reaction
catalyzed by 1. Other ruthenium catalysts such as Ru3-
(CO)12, Cp*Ru(PPh3)2Cl, and Cp*Ru(COD)Cl surveyed in
Table 1 did not exhibit a similar degree of solvent control in
forming the coupling products.
(10) Selected review articles: (a) Bruneau, C.; Dixneuf, P. H. Acc.
Chem. Res. 1999, 32, 311–323. (b) Drozdak, R.; Allaert, B.; Ledoux, N.;
Dragutan, I.; Dragutan, V.; Verpoort, F. Adv. Synth. Catal. 2005, 347, 1721–
1743.
(11) (a) Bianchini, C.; Meli, A.; Peruzzini, M.; Zanobini, F.; Bruneau,
C.; Dixneuf, P. H. Organometallics 1990, 9, 1155–1160. (b) Doucet, H.;
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Hofer, J.; Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1993, 850–851. (c)
Melis, K.; Opstal, T.; Verpoort, F. Eur. J. Org. Chem. 2002, 3779–3784. (d)
Nakagawa, H.; Okimoto, Y.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2003,
44, 103–106. (e) Hua, R.; Tian, X. J. Org. Chem. 2004, 69, 5782–5784. (f)
Doherty, S.; Knight, J. G.; Rath, R. K.; Clegg, W.; Harrington, R. W.; Newman,
C. R.; Campbell, R.; Amin, H. Organometallics 2005, 24, 2633–2644.
(12) (a) Mitsudo, T.; Hori, Y.; Yamakawa, Y.; Watanabe, Y. J. Org.
Chem. 1987, 52, 2230–2239. (b) Ho, J. H. H.; Black, D. S.; Messerle, B. A.;
Clegg, J. K.; Turner, P. Organometallics 2006, 25, 5800–5810.
(13) Doucet, H.; Martin-Vaca, B.; Bruneau, C.; Dixneuf, P. H.
J. Org. Chem. 1995, 60, 7247–7255.
It is imperative to briefly mention the recent advances in
using solvents with different polarity and coordinating abil-
ity to control the product selectivity. Coordinatively unsa-
turated transition metal complexes have been found to be
particularly sensitive to the nature of solvents in mediating
unreactive bond activation reactions.18-20 For example,
ꢀ
(14) Le Paih, J.; Monnier, F.; Derien, S.; Dixneuf, P. H.; Clot, E.;
Eisenstein, O. J. Am. Chem. Soc. 2003, 125, 11964–11975.
(15) (a) Cherry, K.; Parrain, J.-L.; Thibonnet, J.; Duchene, A.;
Abarbri, M. J. Org. Chem. 2005, 70, 6669–6675. (b) Wang, Y.; Burton,
D. J. J. Org. Chem. 2006, 71, 3859–3862. (c) Ueura, K.; Satoh, T.; Miura, M.
Org. Lett. 2007, 9, 1407–1409. (d) Kim, H.; Goble, S. D.; Lee, C. J. Am.
Chem. Soc. 2007, 129, 1030–1031.
^
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4528–4529. (b) Feller, M.; Iron, M. A.; Shimon, L. J. W.; Diskin-Posner, Y.;
Leitus, G.; Milstein, D. J. Am. Chem. Soc. 2008, 130, 14374–14375.
(19) Swartz, B. D.; Reinartz, N. M.; Brennessel, W. W.; Garca, J. J.;
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Inorg. Chim. Acta 2009, 362, 97–104.

Article
Organometallics, Vol. 28, No. 22, 2009 6587
Table 1. Catalyst Survey on the Coupling Reaction of Benzoic
Acid and 4-Ethynylanisolea
entry
catalyst
yield (%)b
2a:(Z)-3a:(E)-3a
1
2
3
4
5
6
7
8
9
(PCy3)2(CO)RuHCl (1)
(PPh3)3(CO)RuH2
(PPh3)3RuCl2
>95
0
100:0:0
0
0
0
0
90
50
60
(PPh3)3RuHCl
RuCl3 3H2O
3
[RuCl2(COD)]x
Ru3(CO)12
8:17:75
15:50:35
22:78c
Cp*Ru(PPh3)2Cl
Cp*Ru(COD)Cl
a Reaction conditions: benzoic acid (0.10 mmol), 4-ethynylanisole
(0.15 mmol), catalyst (2 mol %), CH2Cl2 (2 mL), 95 °C, 8 h. b GC yields
based on benzoic acid. c Ratio of 2a and 1:2 coupling products.
Figure 1. Plot of the initial rate (vi) vs [PCy3] for the coupling
reaction of benzoic acid and phenylacetylene.
Table 2. Solvent Effect on the Coupling Reaction of Benzoic Acid
and 4-Ethynylanisole Catalyzed by 1a
Scheme 1
entry
solvent
2a:(Z)-3a:(E)-3a
yield (%)b
1
2
3
4
5
6
7
8
9
10
benzene
toluene
n-hexane
CH2Cl2
Et2O
CH3CN
DME
DMSO
H2O
THF
51:40:9
68:26:6
71:18:11
99:1:0
13:20:67
33:55:13
5:74:21
2:48:50
3:44:53
0:100:0
80
70
75
>99
60
55
50
53
73
>99
a Reaction conditions: benzoic acid (0.10 mmol), 4-ethynylanisole
(0.15 mmol), 1 (14 mg, 2 mol %), solvent (2 mL), 95 °C, 8 h. b GC yields
based on benzoic acid.
Milstein discovered a remarkable solvent effect of the pincer-
ligated (PCP)Rh complexes in directing C-H vs C-C bond
and C-I vs C-CN bond activation reactions.18 Jones
investigated the similar solvent control effects in C-C vs
C-H bond cleavage reactions of alkenyl nitriles by using
well-defined Ni-diphosphine complexes.19 The regioselectiv-
ity of a number of synthetically useful catalytic coupling
reactions of alkenes and alkynes, such as Heck-type and
allylic substitution reactions, has also been successfully
controlled by using different solvents.20
The scope of the coupling reaction was surveyed in both
CH2Cl2 and THF by using the catalyst 1 (Table 3). An
excellent degree of solvent control was observed for the
coupling reaction of terminal alkynes with carboxylic acids
in facilitating regio- and stereoselective formation of the enol
ester products. Thus, the coupling reaction in CH2Cl2 led to
the exclusive formation of the gem-enol ester product 2 for
both aliphatic and aryl-substituted terminal alkynes. In
contrast, the coupling reaction for aryl-substituted alkynes
in THF predominantly gave the (Z)-enol ester products
(Z)-3. The electronic nature of the alkynes was found to be
an important factor in dictating regioselective product for-
mation, since gem-enol ester product 2 was formed predo-
minantly with the aliphatic terminal alkynes, even when the
reaction was performed in THF (entries 17-19, 32, 34). In all
cases, a relatively low catalyst loading (1-2 mol %) was used
for the coupling reaction, and the enol ester products were
readily isolated in high yields after a simple column chroma-
tography on silica gel.
reaction of carboxylic acids with propargylic alcohols to give
the acetomethyl ester products 4 in high yields. In these cases,
exclusive formation of the ketone product was formed from
the Markovnikov-selective hydration of the alkynes. Such
Markovnikov selectivity has been generally preferred for the
hydration of terminal alkynes,21 although anti-Markovni-
kov selective hydration of alkynes has been achieved more
recently by using late transition metal catalysts.22 The ana-
logous coupling reaction with an aryl-substituted diyne 1,4-
diethynylbenzene in CH2Cl2 predictably yielded the corre-
sponding gem-dienol diester product 5a (entry 8), while a
mixture of gem-, (E)-, and (Z)-dienol diester products was
formed in THF (gem:E:Z = 18:32:50, 91% combined yield).
In contrast, an aliphatic diyne produced gem-dienol diester
5b exclusively in both CH2Cl2 and THF (entry 9).
Mechanistic Study: Phosphine Inhibition Study. The fol-
lowing experiments were performed to probe the factors
influencing the formation of the enol ester products. First,
the phosphine inhibition kinetics was measured from the
(21) (a) Bruce, M. I. Chem. Rev. 1991, 91, 197–257. (b) Tani, K.;
Kataoka, Y. In Catalytic Heterofunctionalization; Togni, A., Gr€utzmacher,
H., Eds.; VCH-Wiley: Weinheim, 2001; pp 199-207. (c) Bruneau, C.;
Dixneuf, P. H. Angew. Chem., Int. Ed. 2006, 45, 2176–2203.
(22) (a) Grotjahn, D. B.; Incarvito, C. D.; Rheingold, A. L. Angew.
Chem., Int. Ed. 2001, 40, 3884–3887. (b) Tokunaga, M.; Suzuki, T.; Koga,
N.; Fukushima, T.; Horiuchi, A.; Wakatsuki, Y. J. Am. Chem. Soc. 2001,
123, 11917–11924. (c) Grotjahn, D. B.; Lev, D. A. J. Am. Chem. Soc. 2004,
126, 12232–12233. (d) Labonne, A.; Kribber, T.; Hintermann, L. Org. Lett.
2006, 8, 5853–5856.
To further demonstrate the synthetic efficacy of the ruthe-
nium catalyst 1, we next examined the coupling reaction of
carboxylic acids with both propargylic alcohols and diynes
(Table 4). The catalyst 1 was found to catalyze the coupling

6588 Organometallics, Vol. 28, No. 22, 2009
Table 3. Alkyne-to-Carboxylic Acid Coupling Reactiona
Yi and Gao
a Reaction conditions: acid (1.0 mmol), alkyne (2.0 mmol), 1 (14 mg, 2 mol %), solvent (2-3 mL), 90-95 °C, 8-12 h. bIsolated yield.
coupling reaction of benzoic acid and phenylacetylene in the
presence of the catalyst 1 (2 mol %). The plot of the initial
rate (vi), which was estimated from a first-order plot of
ln[product] vs reaction time, as a function of [PCy3] showed
that the rate is inversely dependent on added [PCy3]
(Figure 1). The addition of PCy3 (10-30 mM, 2.5-7.5 mol
%) to the reaction mixture under otherwise similar condi-
tions led to a steady decrease from kobs = 1.8 ꢀ 10-2 h-1
(without added PCy3) to 4.0 ꢀ 10-3 h-1 (30 mM of PCy3).
These results indicate that the active Ru catalyst is formed by
a reversible dissociation of the phosphine ligand.
Deuterium Labeling Study. The treatment of PhCO2D with
PhCtCH (2.0 equiv) and 1 (2 mol %) in CH2Cl2 at 95 °C
yielded the gem-enol ester product 2c with ca. 30% D on both
vinyl positions, as determined by 1H and 2H NMR
(Scheme 1). The analogous reaction in THF also formed
the product (Z)-3c with a similar amount of deuterium on the
vinyl positions. Conversely, the reaction of PhCO2H with
PhCtCD (2 equiv) in CH2Cl2 and in THF formed the
products 2c and (Z)-3c, respectively, with nearly equal
amounts of the deuterium (62-67%) on the vinyl positions.
In a control experiment, the treatment of PhCO2D with
PhCtCH (2.0 equiv) in the presence of 1 (2 mol %) led to
almost complete H/D exchange within 10 min at 95 °C prior
to the product formation. The ruthenium catalyst was found
to be essential for the H/D exchange reaction, since no
significant H/D exchange between PhCO2D and PhCtCH
occurred in the absence of 1 under otherwise similar
conditions. These results indicate that the H/D exchange
between the acid and alkynyl hydrogens is rapid and rever-
sible and that neither the alkynyl C-H bond nor the
carboxylic acid O-H bond activation step is a rate-limiting
step of the coupling reaction.
Hammett Study. To discern the electronic effects on the
product formation, the Hammett F values were measured for
the coupling reaction in both CDCl3 and THF. Thus, the
correlation of relative rates with σp for a series of para-
substituted benzoic acids p-X-C6H4CO2H (X = OMe, CH3,
H, CF3, CN) with phenylacetylene in the presence 1 (2 mol
%) at 95 °C led to the opposing trend between the reaction in
CDCl3 (F = þ0.30) and in THF (F = -0.68) (Figure 2).9b An
analogous correlation of the reaction rates of benzoic acid
with a series of para-substituted alkynes p-Y-C6H4CtCH
(Y = OMe, CH3, H, F, CF3) also resulted in the opposite
slope between two solvents (F = -0.57 in CDCl3 vs F =
þ0.33 in THF) (Figure 3).
The opposite Hammett F value indicates a different
mechanistic pathway between the coupling reaction in
CDCl3 and in THF. The positive F value observed
from the correlation of para-substituted benzoic acids
p-X-C6H4CO2H in CDCl3 matches well with a direct migra-
tory insertion of the carboxylate group to a coordinated
terminal alkyne, which is dictated by the nucleophilicity of a
developing negative charge on the carboxylic oxygen. On the
other hand, a negative F value obtained from the reaction in
THF indicates considerable cationic character buildup on the

Article
Organometallics, Vol. 28, No. 22, 2009 6589
Table 4. Coupling Reaction of Carboxylic Acids with Propargylic
Alcohols and Diynesa
Figure 2. Hammett plots of the coupling reaction of para-
substituted p-X-C6H4CO2H (X = OMe, CH3, H, CF3, CN)
with phenylacetylene in CDCl3 (b) and in THF (9).
a Reaction conditions: carboxylic acid (1.0 mmol), alkyne (2.0 mmol),
1 (14 mg, 2 mol %), CH2Cl2 (2-3 mL), 90-95 °C, 8-12 h. bIsolated
yield. c48 h of the reaction time.
Figure 3. Hammett plots of the coupling reaction of benzoic
acid with para-substituted p-Y-C6H4CtCH (Y = OMe, CH3,
H, F, CF3) in CDCl3 (b) and in THF (9).
transition state, and this can be explained via the formation
of the Ru-vinylidene species, wherein electrophilic character
of the R-vinylidene carbon has been well established.10a,21a
The analogous opposite trend from the correlation of the
alkynes p-Y-C6H4CtCH can similarly be rationalized in
terms of developing a positive charge on the alkynyl carbon.
Thus, a negative F value in CDCl3 is consistent with the
positive charge buildup on the internal alkynyl carbon, while
a positive F value in THF suggests an electrophilic character
on the terminal alkynyl carbon. Once again, the latter case is
consistent with the formation of a Ru-vinylidene species and
the addition of the carboxylate group to the electrophilic R-
vinylidene carbon in the transition state.
In an effort to form a catalytically relevant ruthenium-
vinylidene complex, the reaction of the ruthenium-carboxylate
complex 6 with terminal alkynes was performed in THF.
Thus, the treatment of complex 6 (44 mg, 0.050 mmol) with
phenylacetylene (1.2 equiv) in THF at 95 °C for 10 h led to
the coupling product 7, which was isolated in 85% yield as a
pale yellow-colored solid. The 1H NMR of complex 7
showed a diagnostic vinyl peak at δ 6.24 (br s), and two
distinct R-carbonyl peaks at δ 208.8 (t, JCP = 14.4 Hz, Ru-
CO) and 190.2 (t, JCP = 12.1 Hz, Ru-C(O)CHPh) were also
observed by the 13C{1H} NMR.
The molecular structure of 7 as determined by X-ray crystal-
lography showed a syn orientation between the carboxylate
oxygen atom and the phenyl group that apparently resulted
from the coupling between the carboxylate and the vinylidene
ligands (Figure 5). The structure clearly implicates the forma-
tion of the (Z)-enol ester product (Z)-3k from the protonation
by another carboxylic acid. To show the enol ester product
formation, the complex 7 was treated with an equivalent of
benzoic acid in THF, which produced the carboxylate complex
6 and (Z)-3k along with another unidentified ruthenium
complex upon heating at 90 °C for 2 h. Furthermore, the
activity of both complexes 6 and 7 was found to be virtually
identical to 1 for the coupling reaction of benzoic acid and
phenylacetylene in THF (>90% yield with 2 mol % of 7).
The successful isolation of the catalytically relevant
complexes 6 and 7 enabled us to further examine the ki-
netics for the formation of these complexes. The treatment
of 1 (14 mg, 0.020 mmol) with excess amounts of p-OMe-
C6H4CO2H (10 equiv) and HCtCPh (15 equiv) in THF
was followed by 1H and 31P NMR (Scheme 2). As ex-
pected, the formation of the previously synthesized
Catalytically Relevant Ruthenium-Carboxylate and -Viny-
lidene-Carboxylate Complexes. A catalytically relevant
ruthenium-carboxylate complex was successfully isolated
from the reaction of 1 with a carboxylic acid. For example,
the treatment of 1 (72 mg, 0.10 mmol) with p-OMe-
C6H4CO2H (16 mg, 0.11 mmol) in CH2Cl2 (2 mL) at room
temperature for 10 h led to the clean formation of the
ruthenium-carboxylate complex 6, which was isolated in
87% yield after recrystallization in CH2Cl2/hexanes. The
complex 6 exhibited two sets of aryl protons at δ 7.88 (d, J =
8.7 Hz) and 6.89 (d, J = 8.7 Hz) in the 1H NMR, as well as
two carbonyl peaks at δ 208.8 (t, JCP = 13.3 Hz, CO) and
179.0 (s, CO2) in the 13C{1H} NMR. A single phosphine peak
at δ 28.7 was also observed by the 31P{1H} NMR. The
structure of 6 was further established by X-ray crystallogra-
phy (Figure 4). The molecular structure showed a pseudooc-
tahedral geometry around the ruthenium center with trans
phosphine and cis CO and Cl- ligand arrangements. A
slightly larger than 90° bond angle between CO and Cl-
ligands (96.4°) may be due to a κ2-bonding mode of the
carboxylate ligand.

6590 Organometallics, Vol. 28, No. 22, 2009
Yi and Gao
Figure 5. Molecular structure of 7.
Figure 4. Molecular structure of 6.
ruthenium-vinyl complex 8 was observed after 15 min at
room temperature.23 Upon warming to 40 °C, the vinyl com-
plex 8 was slowly converted to the carboxylate complex 6
within 10 min along with the formation of styrene. At 60 °C, the
signals due to the vinylidene-carboxylate complex 7 gradually
appeared at the expense of the carboxylate complex 6. Even-
tually, the formation of the coupling product (Z)-3k along with
Scheme 2
Figure 6. Kinetic profile of the conversion of 8 to 7. Notations:
8 (2), 6 (b), 7 (9).
carboxylate oxygen to the internal carbon of the alkyne sub-
strate would be preferred over the terminal one to give the gem-
enol ester product 2. The dative coordination of the carboxylic
oxygen atom would also promote the insertion by stabilizing
intermediate species. On the other hand, the formation of (Z)-
enol ester product (Z)-3 is rationalized by invoking the forma-
tion of Ru-vinylidene species 10. It has been well-established
that the acetylene-to-vinylidene rearrangement is relatively
facile for aryl-substituted alkynes.10,21 The ability to promote
the acetylene-to-vinylidene rearrangement for the ruthenium
catalyst should be an important factor for the stereoselective
formation of (Z)-enol ester products, and the coordinating
solvent THF would facilitate such rearrangement by stabilizing
a coordinatively unsaturated Ru-vinylidene species.
The Hammett study suggested that the C-O bond forma-
tion of the catalytic coupling reaction is strongly influenced
by the electronic nature of the substrates. For the coupling
reaction in CH2Cl2, this implies a direct migratory insertion
of the coordinated terminal alkyne to the Ru-carboxylic
oxygen bond, where both steric and electronic factors dictate
the Markovnikov-selective formation of the gem-enol ester
product 2. The dative coordination of the carbonyl oxygen to
the Ru center would also facilitate this transformation by
avoiding the formation of a high-energy 14-electron species.
The successful isolation of 6 and 7 and their kinetic
reaction profile provided new mechanistic insights for the
formation of (Z)-enol ester product (Z)-3. The reversible
dissociation of PCy3 from both complexes 6 and 7 should
form the catalytically active species for the coupling reaction,
Cy3PHþPhCO2- was observed after heating at 90 °C for 2 h.
The kinetics of the conversion of the vinyl complex 8 to the
vinylidene-carboxylate complex 7 was followed by 31P NMR
(Figure 6). In a J-Young NMR tube, 1 (14 mg, 0.020 mmol),
4-methoxybenzoic acid (30 mg, 0.20 mmol), and phenylace-
tylene (31 mg, 0.30 mmol) were dissolved in THF (0.5 mL).
The formation of the vinyl complex 8 was completed within
10 min at room temperature. The appearance of 6 and 7 was
monitored by 31P NMR at 60 °C in 5 min intervals. The ex-
perimental data were successfully fitted to the kinetic equa-
tion for two consecutive reaction kinetics by using nonlinear
regression techniques for the conversion of 8 to 7 (Sigma-
plot Version 10).24 The rate constants k1= 0.039 min-1 and
k2 = 0.013 min-1 were obtained from this analysis. A rela-
tively smaller value of k2 compared to k1 is consistent with
the rate-limiting C-O bond formation step.
Proposed Mechanism. We propose a mechanism of the
coupling reaction involving a coordinatively unsaturated
ruthenium-carboxylate complex 9 as one of the key intermedi-
ate species (Scheme 3). The phosphine inhibition study suggests
that the catalytically active 16 e- complex 9 is formed from the
Ru-carboxylate complex 6 by a reversible phosphine disso-
ciation. For the coupling reaction in a noncoordinating
solvent such as CH2Cl2, the direct migratory insertion of the
(23) (a) Yi, C. S.; Lee, D. W.; Chen, Y. Organometallics 1999, 18,
2043–2045. (b) Yi, C. S.; Lee, D. W. Organometallics 1999, 18, 5152–5156.
(24) See Supporting Information for the derivation of the kinetic
equation.

Article
Organometallics, Vol. 28, No. 22, 2009 6591
Scheme 3. Proposed Mechanism of the Coupling Reaction of Carboxylic Acids and Terminal Alkynes
and in this regard, the formation of Cy3PHþ from the
protonation of free PCy3 by the carboxylic acid substrate
would prohibit the recoordination of the phosphine ligand to
the Ru center. The syn geometry of the vinylidene-carbox-
ylate ligand of 7 clearly indicates that the formation of (Z)-
enol ester product (Z)-3 is electronically controlled during
the addition of a carboxylate group to the R-vinylidene
ligand of the ruthenium-vinylidene species 10. Such cis
addition of the carboxylate group could also be facilitated
by the dative coordination of the carboxylate oxygen atom.
A complementary computational study on the catalytic
coupling reaction would be prudent in identifying these
catalytically active intermediate species.
benzene, hexanes, and Et2O were distilled from purple solutions
of sodium and benzophenone immediately prior to use. The NMR
˚
solvents were dried from activated molecular sieves (4 A). All
carboxylic acid and alkyne substrates were received from com-
mercial sources and used without further purification. RuCl3
3
3H2O and Ru3(CO)12 were obtained from commercial sources,
and the complex 1 was prepared by following a reported proce-
dure.23 The 1H, 2H, 13C, and 31P NMR spectra were recorded on a
Varian Mercury 300 or 400 MHz FT-NMR spectrometer. Mass
spectra were recorded from a Agilent 6850 GC/MS spectrometer.
The conversion of organic products was measured from a Hew-
lett-Packard HP 6890 GC spectrometer. Elemental analyses were
performed at the Midwest Microlab, Indianapolis, IN.
General Procedure of the Catalytic Reaction. In a glovebox, a
carboxylic acid (1.0 mmol), a terminal alkyne (2.0 mmol), and
the ruthenium catalyst 1 (14 mg, 2 mol %) were dissolved in
3 mL of CH2Cl2 (or THF) in a 25 mL Schlenk tube equipped
with a Teflon stopcock and a magnetic stirring bar. The reaction
tube was brought out of the box and was stirred in an oil bath at
90-95 °C for 10-12 h. The tube was opened to air at room
temperature, and the crude product mixture was analyzed by
GC. An analytically pure organic product was isolated by a
column chromatography on silica gel (hexanes/EtOAc). While
we have not encountered any problems, the reaction in CH2Cl2
must be carried out with extra caution because of its relatively
low boiling point. A thick-walled Schlenk tube with enough
volume reservoir is strongly recommended.
Concluding Remarks
The ruthenium-hydride complex 1 was found to be a
highly effective catalyst for the alkyne-to-carboxylic acid
coupling reaction to give synthetically valuable enol esters.
Regio- and stereoselectivity of the catalyst 1 was successfully
controlled by using CH2Cl2 and THF. From a synthetic
point of view, the ruthenium catalyst 1 exhibited a number of
salient features including its ability to control the activity and
selectivity on the enol ester product formation with a rela-
tively low catalyst loading, and a broad substrate scope
under relatively moderate reaction conditions. The kinetic
and mechanistic investigations as well as the successful
isolation of Ru-carboxylate and -vinylidene-carboxylate
complexes 6 and 7 provided a detailed mechanistic picture
for the coupling reaction. The mechanistic knowledge gained
from this study should give invaluable insights in designing
the next generation of metal catalysts for the alkyne-to-
carboxylic acid coupling reaction.
Phosphine Inhibition Study. In a glovebox, benzoic acid (24
mg, 0.20 mmol), phenylacetylene (40 mg, 0.40 mmol), 1 (3 mg, 2
mol %), and C6Me6 (5 mg, internal standard) were dissolved in
CDCl3 (0.5 mL) in a J-Young NMR tube with a Teflon screw
cap. A predissolved PCy3 in CDCl3 solution (5-15 μL, 10-30
mM) was added to the tube via syringe. The tube was brought
out of the glovebox and was heated in an oil bath at 95 °C. The
1
reaction was monitored by H NMR in 30 min intervals. The
rate was measured by the 1H integration of the product peak at
δ 5.61 (dCH2) and was normalized against the internal standard
peak. The kobs was estimated from the first-order plot of
ln[product] vs reaction time.
Experimental Section
Isotope Labeling Study. In a glovebox, benzoic acid (122 mg,
1.0 mmol) and DCtCPh (206 mg, 2.0 mmol) were added via
syringe to a 25 mL Schlenk tube equipped with a magnetic
General Information. All operations were carried out in a
nitrogen-filled glovebox or by using standard high-vacuum and
Schlenk techniques unless otherwise noted. Tetrahydrofuran,

6592 Organometallics, Vol. 28, No. 22, 2009
Yi and Gao
stirring bar and Teflon stopcock. The predissolved catalyst 1
(14 mg, 2 mol %) in CH2Cl2 or THF (3 mL) was added to the
reaction tube. The reaction tube was brought out of the box and
was stirred in an oil bath at 95 °C for 10 h. The solvent was
removed from a rotary evaporator, and the organic product was
isolated by column chromatography on silica gel (hexanes/
CH2Cl2, 3:2). The deuterium content of the products 2c and 3c
was measured from both 1H NMR (CDCl3 with 10 mg of
Synthesis of (PCy3)2(CO)(Cl)Ru(K2-O2CC6H4-p-OMe) (6).
In a glovebox, 4-methoxybenzoic acid (13 mg, 0.10 mmol),
phenylacetylene (10 mg, 0.10 mmol), and complex 1 (73 mg,
0.10 mmol) were dissolved in CH2Cl2 (3 mL) in a 25 mL Schlenk
tube equipped with a Teflon screw cap stopcock and a magnetic
stirring bar. The tube was brought out of the box and was stirred
at room temperature for 10 h. The solvent was evaporated, and
the residue was washed with hexanes (3 mL ꢀ 3 times) to obtain
6 in 87% yield. Single crystals suitable for X-ray crystallo-
graphic study were obtained from hexanes/CH2Cl2.
2
cyclohexane as the external standard) and H NMR (CH2Cl2
with 50 μL of CDCl3).
Hammett Study: Reaction in CDCl3. In a glovebox, a para-
substituted acid p-X-C6H4CO2H (X = OMe, CH3, H, CF3, CN)
(0.20 mmol), phenylacetylene (40 mg, 0.40 mmol), 1 (3 mg,
2 mol %), and C6Me6 (5 mg, internal standard) were dis-
solved in CDCl3 (0.5 mL) solution in a J-Young NMR tube
with a Teflon screw cap. The tube was brought out of the
glovebox and was heated in an oil bath set at 95 °C. The reaction
For 6: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.7 Hz, Ph),
6.89 (d, J = 8.7 Hz, Ph), 3.86 (s, OCH3), 2.30-1.01 (m, PCy3);
13C{1H} NMR (100 MHz, CDCl3) δ 208.8 (t, JCP = 13.3 Hz,
CO), 179.0 (s, CO2), 162.9, 130.3, 125.1, and 113.6 (CAr), 55.5
(OCH3), 34.1, 30.2, 29.7, 28.3, and 26.8 (PCy3); 31P{1H} NMR
(161 MHz, CDCl3) δ 28.7 (s, PCy3); IR (KBr) νCO 1913 cm-1
.
Synthesis of (PCy3)2(CO)(Cl)RuC(dCHPh)O2CC6H4-p-
OMe (7). In a glovebox, the Ru-carboxylate complex 6 (44
mg, 50 μmol) and phenylacetylene (6 mg, 60 μmol) were
dissolved in THF (3 mL) in a 25 mL Schlenk tube equipped
with a Teflon screw cap stopcock and a magnetic stirring bar.
The tube was brought out of the glovebox and was heated in an
oil bath at 95 °C for 10 h. The solvent was removed under high
vacuum, and the residue was washed with hexanes (5 mL ꢀ 3
times) to obtain analytically pure 7 in 85% yield. Single crystals
suitable for X-ray crystallographic study were obtained from
hexanes/CH2Cl2.
1
was monitored by H NMR in 10 min intervals. The kobs was
estimated from a first-order plot of ln[product] vs reaction time
by measuring the H integration of the product peak (dCH2,
1
δ 5.61 ppm), which was normalized against the internal standard
peak.
Reaction in THF. In a 25 mL Schlenk tube equipped with a
Teflon stopcock and a magnetic stirring bar, a para-substituted
acid p-X-C6H4CO2H (X=OMe, CH3, H, CF3, CN) (1.0 mmol),
phenylacetylene (200 mg, 2.0 mmol), 1 (14 mg, 2 mol %), and
C6Me6 (26 mg, internal standard) were dissolved in THF
(3 mL) in a glovebox. The tube was brought out of the glovebox
and was heated in an oil bath at 95 °C. The reaction was
monitored by GC in 10 min intervals. The kobs was estimated
from a first-order plot of ln[product] vs reaction time by
measuring the amount of the products against the internal
standard.
Kinetic Profile Experiment. In a glovebox, 1 (14 mg, 0.02
mmol), 4-methoxybenzoic acid (30 mg, 0.20 mmol), and
HCtCPh (31 mg, 0.30 mmol) were dissolved in THF (0.5 mL)
in a J-Young NMR tube with a Teflon screw cap. The tube was
brought out of the glovebox and was placed in NMR probe,
which was preset at 60 °C. The appearance and disappearance of
the phosphine signals for 8 (δ 24.4), 6 (δ 25.9), and 7 (δ 23.4)
were monitored by 31P NMR at 60 °C in 5 min intervals. The rate
of the product formation was determined by measuring the
integration of the product peaks against the disappearance of
the complex 8. By using a nonlinear regression technique
(Sigmaplot Version 10), the experimental data were globally
fitted to the kinetic equation as shown in Figure 6. The rate
constants k1= 0.039 min-1 and k2 = 0.013 min-1 were obtained
from this analysis.
For 7: 1H NMR (400 MHz, C6D6) δ 8.44 (d, J = 8.7 Hz, 2H,
Ph), 7.76 (d, J = 7.7 Hz, 2H, Ph), 7.36-6.63 (m, Ar), 7.76 (d,
J = 7.7 Hz, 2H, Ar), 7.36-6.63 (m, Ph); 13C{1H} NMR (100
MHz, CDCl3) δ 209.8 (t, JPC = 14.4 Hz, CO), 190.2 (t, JPC
=
12.2 Hz, Ru-CdCH), 173.8 (CO2), 167.9, 165.4, 138.4, 133.8,
129.1, 125.0, 122.5, and 120.0 (CAr), 115.1 (dCH), 55.4 (OCH3),
35.2, 31.1, 30.6, 29.8, 28.8, and 27.3 (PCy3); 31P{1H} NMR (161
MHz, CDCl3) δ 27.0 (s, PCy3); IR (KBr) νCO 1922 cm-1
.
Acknowledgment. Financial support from the Na-
tional Institute of Health, General Medical Sciences
(R15 GM55987), is gratefully acknowledged. We also
thank Dr. Sergey Lindeman (Marquette University) for
X-ray crystallographic determination of the ruthenium
complexes.
Supporting Information Available: Spectroscopic data of
organic products and X-ray crystallographic data of 6 and 7.
This material is available free of charge via the Internet at http://
pubs.acs.org.